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Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer

Zetterberg, Fredrik R. ; Peterson, Kristoffer ; Nilsson, Ulf J. LU ; Andréasson Dahlgren, Kajsa ; Diehl, Carl ; Hoyler, Ian ; Håkansson, Maria ; Khabut, Areej LU ; Kahl-Knutson, Barbro LU and Leffler, Hakon LU , et al. (2024) In Journal of Medicinal Chemistry 67(11). p.9374-9388
Abstract
We have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells... (More)
We have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC50 = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over galectin-1 Kd for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
67
issue
11
pages
15 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:38804039
  • scopus:85194404639
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.4c00485
language
English
LU publication?
yes
id
236045e0-059c-48f5-8942-1091ea1476bd
date added to LUP
2024-05-30 17:22:16
date last changed
2025-07-08 23:18:45
@article{236045e0-059c-48f5-8942-1091ea1476bd,
  abstract     = {{We have previously described a new series of selective and orally available galectin-1 inhibitors resulting in the thiazole-containing glycomimetic GB1490. Here, we show that the introduction of polar substituents to the thiazole ring results in galectin-1-specific compounds with low nM affinities. X-ray structural analysis of a new ligand-galectin-1 complex shows changes in the binding mode and ligand-protein hydrogen bond interactions compared to the GB1490-galectin-1 complex. These new high affinity ligands were further optimized with respect to affinity and ADME properties resulting in the galectin-1-selective GB1908 (<i>K</i><sub>d</sub> galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC<sub>50</sub> = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over galectin-1 <i>K</i><sub>d</sub> for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.}},
  author       = {{Zetterberg, Fredrik R. and Peterson, Kristoffer and Nilsson, Ulf J. and Andréasson Dahlgren, Kajsa and Diehl, Carl and Hoyler, Ian and Håkansson, Maria and Khabut, Areej and Kahl-Knutson, Barbro and Leffler, Hakon and MacKinnon, Alison C. and Roper, James A. and Slack, Robert J. and Zarrizi, Reihaneh and Pedersen, Anders}},
  issn         = {{1520-4804}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{11}},
  pages        = {{9374--9388}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.4c00485}},
  doi          = {{10.1021/acs.jmedchem.4c00485}},
  volume       = {{67}},
  year         = {{2024}},
}